RESUMO
Epigenetic regulation of gene expression, through covalent modification of histones, is a key process controlling growth and development. Accordingly, the transcription factors regulating these processes are important targets of genetic diseases. However, surprisingly little is known about the relationship between aberrant epigenetic states, the cellular process affected, and their phenotypic consequences. By chromosomal breakpoint mapping in a patient with a Noonan syndrome-like phenotype that encompassed short stature, blepharoptosis, and attention deficit hyperactivity disorder, we identified haploinsufficiency of the histone acetyltransferase gene MYST histone acetyltransferase (monocytic leukemia) 4 (MYST4), as the underlying cause of the phenotype. Using acetylation, whole genome expression, and ChIP studies in cells from the patient, cell lines in which MYST4 expression was knocked down using siRNA, and the Myst4 querkopf mouse, we found that H3 acetylation is important for neural, craniofacial, and skeletal morphogenesis, mainly through its ability to specifically regulating the MAPK signaling pathway. This finding further elucidates the complex role of histone modifications in mammalian development and adds what we believe to be a new mechanism to the pathogenic phenotypes resulting from misregulation of the RAS signaling pathway.
Assuntos
Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Síndrome de Noonan/genética , Animais , Criança , Mapeamento Cromossômico , Análise Mutacional de DNA , Epigênese Genética , Técnicas de Silenciamento de Genes , Haploinsuficiência , Células HeLa , Histonas/metabolismo , Humanos , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Morfogênese/genética , Síndrome de Noonan/patologia , Síndrome de Noonan/fisiopatologia , Fenótipo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismoRESUMO
We identified a maternally inherited 14.2Mb duplication 5q22.1-q23.2 in two female siblings and their mother by molecular karyotyping. Both siblings were small for gestational age and presented with pronounced postnatal growth retardation, mild motor delay, congenital heart disease in one of the siblings, and distinct facial dysmorphism. As this duplication is one of the smallest reported 5q duplications, short stature and facial dysmorphism can be attributed to duplications of 5q22, whereas severe mental retardation is not part of the phenotypic spectrum of the 5q22.1-q23.2 region. Congenital heart defects, as observed in other 5q duplications, have a variable penetrance. We compared the facial features of patients with 5q duplications and found some consistent features such as high arched eyebrows, bulbous nasal tip and small lips with thin vermilion border.
Assuntos
Síndrome de Cri-du-Chat/genética , Transtornos do Crescimento/genética , Trissomia/genética , Adolescente , Criança , Bandeamento Cromossômico , Cromossomos Humanos Par 5/genética , Feminino , Estudo de Associação Genômica Ampla , Cardiopatias Congênitas/genética , Humanos , Hibridização in Situ Fluorescente , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Xq28 duplications including MECP2 are a well-known cause of severe mental retardation in males with seizures, muscular hypotonia, progressive spasticity, poor speech and recurrent infections that often lead to early death. Female carriers usually show a normal intellectual performance due to skewed X-inactivation (XCI). We report on two female patients with a de novo MECP2 duplication associated with moderate mental retardation. In both patients, the de novo duplication occurred on the paternal allele, and both patients show a random XCI, which can be assumed as the triggering factor for the phenotype. Furthermore, we describe the phenotype that might be restricted to unspecific mild-to -moderate mental retardation with neurological features in early adulthood.